multiple approaches to enantiopure spirocyclic

S1

Multiple approaches to enantiopure spirocyclic benzofuranones using organocatalytic cascade reactions

Carlo Cassani,[a] Xu Tian,[a] Eduardo C. Escudero-Adán,[a] and Paolo Melchiorre*[a,b]

a ICIQ - Institute of Chemical Research of Catalonia, Av. Països Catalans 16 - 43007 Tarragona, Spain b ICREA - Institució Catalana de Recerca i Estudis Avançats, Pg. Lluís Companys 23 - 08010 Barcelona, Spain

e-mail: [email protected] web page: http://www.iciq.es/portal/862/Melchiorre.aspx

Supplementary Information

Supplementary Material (ESI) for Chemical CommunicationsThis journal is (c) The Royal Society of Chemistry 2010

S2

Table of Contents

General S3

Materials S3

Determination of Diastereomeric and Enantiomeric Ratios S4

Structural and absolute configuration determination S4

X-ray Data for compound 3d S4

X-ray Data for compound 6b S6

X-ray Data for compound 8b S7

Influence of the compound 4 geometry on the stereochemical outcome

of the cascade reactions S9

Experimental procedures S10

General Procedure for the Organocatalytic Triple Cascade of Aldehydes proceeding via an

Iminium-Iminium-Enamine Sequence (Table 1) S10

General Procedure for the Organocatalytic Triple Cascade proceeding via enamine – iminium – enamine

activation of aldehydes (Table 2) S14

General Procedure for the Organocatalytic Tandem double Michael additions

(enamine – iminium activation sequence) (Table 3) S17

NMR spectra S21

HPLC Traces S43


S3

General Methods. The 1H and 13C NMR spectra were recorded at 400 MHz and 100 MHz, respectively. The

chemical shifts (δ) for 1H and 13C are given in ppm relative to residual signals of the solvents (CHCl3 @ 7.26

ppm 1H NMR, 77.0 ppm 13C NMR). Coupling constants are given in Hz. Carbon types were determined from

DEPT 13C NMR experiments. The following abbreviations are used to indicate the multiplicity: s, singlet; d,

doublet; t, triplet; q, quartet; m, multiplet; bs, broad signal. Chromatographic purification of products was

accomplished using force-flow chromatography (FC) on silica gel (230-400 mesh) according to the method

of Still.1 For thin layer chromatography (TLC) analysis throughout this work, Merck precoated TLC plates

(silica gel 60 GF254, 0.25 mm) were used, using UV light as the visualizing agent and an acidic mixture of

ceric ammonium molybdate or basic aqueous potassium permangante (KMnO4), and heat as developing

agents. High-resolution mass spectra (HRMS) were obtained from the ICIQ High Resolution Mass

Spectrometry Unit on Waters GCT gas chromatograph coupled time-of-flight mass spectrometer (GC/MS-

TOF) with electron ionisation (EI). X-ray data were obtained from the ICIQ X-Ray Unit using a Bruker-Nonius

diffractometer equipped with an APPEX 2 4K CCD area detector. Optical rotations are reported as follows:

[α]rtD (c in g per 100 mL, solvent). All reactions were set up in the air and using undistilled solvent, without

any precautions to exclude moisture unless otherwise noted.

Materials. Commercial grade reagents and solvents were used without further purification; otherwise,

where necessary, they were purified as recommended.2 Catalysts (S) and (R)-A were purchased from Aldrich

and used as received. Chiral primary amine catalysts, 9-Amino(9-deoxy)epi-hydroquinine B and its pseudo-

enantiomer 9-Amino(9-deoxy)epi-hydroquinidine were prepared from commercially available hydroquinine

and hydroquinidine, respectively, following the literature procedure.3 α,β-unsaturated enones (E)-4-(4-chlorophenyl)but-3-en-2-one 7b and (E)-4-(thiophen-3-yl)but-3-en-2-one

7g, were prepared according to the literature procedure,4 whereas the enal (E)-3-(4-

chlorophenyl)acrylaldehyde 2d was prepared using the Wittig olefination reaction from commercially

available 4-chloro benzaldehyde and (triphenylphosphoranylidene)acetaldehyde.

All the other enals 2, aldehydes 5 and unsaturated ketones 7 were purchased from Aldrich or Alfa Aesar and

used as received. 1-benzofuran-2(3H)-one 1 is commercially available. All the Michael acceptors bearing a benzofuranone moiety (4) were prepared according to literature

procedures.5 3-benzylidenebenzofuran-2(3H)-one 4a was obtained as a 3:1 mixture of E/Z isomer; isolation

of the pure E isomer has been accomplished by standard chromatography on silica gel.

(E)-3-(4-chlorobenzylidene)benzofuran-2(3H)-one, (E)-3-(4-nitrobenzylidene)benzofuran-2(3H)-one, and

(E)-3-butylidenebenzofuran-2(3H)-one were all synthesized as a mixture E/Z isomers, and used without

further purification.

(E)-ethyl 2-(2-oxobenzofuran-3(2H)-ylidene)acetate was synthesized as a single E isomer.

1 W. C. Still, M. Kahn, A. J. Mitra, J. Org. Chem. 1978, 43, 2923. 2 W. L. F. Armarengo, D. D. Perrin, In Purification of Laboratory Chemicals, 4th ed.; Butterworth Heinemann: Oxford, 1996. 3 S. H. McCooey, S. J. Connon. Org. Lett. 2007, 9, 599‐602. 4 K. Zumbansen, A. Döhring, B. List, Adv. Syn. Cat. 2010, 352, 1135‐1138. 5 M. Msaddek, M. Rammah, K. Ciamala, J. Vebrel, B. Laude, Synthesis, 1997, 1495‐1498.


S4

Determination of Enantiomeric Purity. HPLC analysis on chiral stationary phase was performed on an

Agilent 1200-series instrumentation. Daicel Chiralpak IA or IC columns with i-PrOH/hexane as the eluent

were used. HPLC traces were compared to racemic samples prepared by performing the reactions using a

1:1 mixture of (S)- and (R)-A as the catalyst for the synthesis of compounds 3 & 6. Racemic mixtures for

compounds 8 were obtained by mixing the two antipodes obtained performing distinct reactions with

catalyst 9-Amino(9-deoxy)epi-hydroquinine B and the pseudo-enantiomer 9-Amino(9-deoxy)epi-

hydroquinidine.

Determination of Diastereomeric Ratios

The diastereomeric ratio was determined by 1H NMR analysis of the crude reaction mixture, and confirmed

by HPLC analysis on chiral stationary phase columns.

Absolute and Relative Configuration Determination

X-Ray Structure Analysis.

The absolute and relative configurations of compound 3d, 6b, and 8b (Scheme 1) were assigned by X-ray

crystallographic analysis. CCDC 780474, 781708, 781524, respectively, contain the supplementary

crystallographic data for those compounds. These data can be obtained free of charge from the Cambridge

Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif

Single Crystal X-ray Diffraction Data for compound 3d (table 1, entry 5):

X-ray structure determinations: Crystals of compound 3d were obtained by slow evaporation in a mixture of

Hexane and Diethyl-ether in a 1:1 portion at room temperature. The measured crystals were stable under

atmosphere conditions; nevertheless they were prepared under inert conditions immersed in perfluoropoly-

ether as protecting oil for manipulation.

Data Collection. Measurements were made on a Bruker-Nonius diffractometer equipped with an APPEX 2 4K

CCD area detector, a FR591 rotating anode with MoKα radiation, Montel mirrors and a Kryoflex low

temperature device (T = -173 °C). Full-sphere data collection was used with ω and ϕ scans.

Programs used: Data collection Apex2 V2009 1.0 (Bruker-Nonius 2008), data reduction Saint + Version

7.60A (Bruker AXS 2008) and absorption correctionTWINABS.6

Structure Solution. SIR2007 program was used.7

Structure Refinement. SHELXTL-97-UNIX VERSION.

6 TWINABS Version 2008/4 Bruker AXS Blessing, Acta Cryst. (1995) A51 33‐38 7 R.Caliandro, B. Carrozzini, G.L.Cascarano, L. De Caro, C. Giacovazzo and D. Siliqi (2007) Advances in ab initio protein phasing by Patterson deconvolution techniques J. Appl. Cryst. 40,883‐890.


S5

3d

( R) (S)

(R)

H

HCl

O

O

H

ClO

Crystal data for 3d at 100 K: CCDC 780474

Empirical formula C26 H18 Cl2 O3 Formula weight 449.30 Temperature 293(2) K Wavelength 0.71073 Å Crystal system Triclinic Space group P1 Unit cell dimensions a = 9.3195(10) Å α= 82.514(4) °. b = 9.3688(10) Å β = 88.091(4) °. c = 26.301(3) Å γ = 69.752(5) °. Volume 2136.0(4) Å3 Z 4 Density (calculated) 1.397 Mg/m3 Absorption coefficient 0.330 mm-1 F(000) 928 Crystal size 0.30 x 0.30 x 0.10 mm3 Theta range for data collection 0.78 to0.78 °. Index ranges -13 <=h<=14 ,-13 <=k<=14 ,-41 <=l<=41 Reflections collected 29711 Independent reflections 24733 [R(int) = 0.0000 ] Completeness to theta =34.63 ° 0.846 % Absorption correction Empirical Max. and min. transmission 0.9781 and 0.8102 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 29711 / 3 / 1118 Goodness-of-fit on F2 1.052 Final R indices [I>2sigma(I)] R1 = 0.0845 , wR2 = 0.2361 R indices (all data) R1 = 0.0976 , wR2 = 0.2513 Absolute Structure Flack parameter x =0.03( Largest diff. peak and hole 1.627 and -0.747 e.Å-3

The structure refines as a twin made up of two crystal domains with a ratio 71:29. The diffraction measured fraction is

low, 0.89, since the reflections of belonging to both crystal domains have been omitted


S6

6b

(R)

(S)(S)

(R) H

H

O HO

MeH

O

Cl

Single Crystal X-ray Diffraction Data for compound 6b (table 2, entry 3):

X-ray structure determinations: Crystals of compound 6b were obtained by slow evaporation in isopropyl

alcohol at 60ºC. The measured crystals were stable under atmosphere conditions; nevertheless they were

prepared under inert conditions immersed in perfluoropoly-ether as protecting oil for manipulation.

The measured sample is a perfect merohedral twin (twin law 0 1 0 1 0 0 0 0 -1, basf 0.5).

Programs used: Data collection Apex2 V2009 1.0 (Bruker-Nonius 2008), data reduction Saint + Version

7.60A (Bruker AXS 2008) and absorption correctionTWINABS.6

Structure Solution. SIR2007 program was used.7

Crystal data for 6b at 100 K: CCDC 781708

Empirical formula C27 H21 Cl O3

Formula weight 428.89

Temperature 100(2) K

Wavelength 0.71073 Å

Crystal system Tetragonal

Space group P4(1)

Unit cell dimensions a = 9.3547(11) Å α= 90.00 °.

b = 9.3547(11) Å β = 90.00 °.

c = 51.084(6) Å γ = 90.00 °.

Volume 4470.4(9) Å3

Z 8

Density (calculated) 1.274 Mg/m3

Absorption coefficient 0.197 mm-1

F(000) 1792

Crystal size 0.40 x 0.30 x 0.15 mm3

Theta range for data collection 0.80 to 28.23 °.

Index ranges -12 <=h<=9 ,-7 <=k<=12 ,-63 <=l<=67


S7

(S)

(S)

(R)

H

Cl

OH

O

O

8b

Reflections collected 10668

Independent reflections 9044 [R(int) = 0.0714 ]

Completeness to theta =28.23 ° 0.989 %

Absorption correction Empirical

Max. and min. transmission 0.9711 and 0.9255

Refinement method Full-matrix least-squares on F2

Data / restraints / parameters 10668 / 631 / 562

Goodness-of-fit on F2 1.112

Final R indices [I>2sigma(I)] R1 = 0.1074 , wR2 = 0.2585

R indices (all data) R1 = 0.1222 , wR2 = 0.2669

Absolute Structure Flack parameter x =0.08(17)

Largest diff. peak and hole 0.564 and -0.795 e.Å-3 Single Crystal X-ray Diffraction Data for compound 8b (table 3, entry 3):

X-ray structure determinations: Crystals of compound 8b were obtained by slow evaporation in methanol at

room temperature. The measured crystals were stable under atmosphere conditions; nevertheless they were

prepared under inert conditions immersed in perfluoropoly-ether as protecting oil for manipulation.

Crystal data for 8b at 100 K: CCDC 781524

Crystallized from Methanol Empirical formula C25 H19 Cl O3 Formula weight 402.85 Temperature 100(2) K Wavelength 0.71073 Å Crystal system Monoclinic Space group P2(1)


S8

Unit cell dimensions a = 9.3490(9) Å α= 90.00 °. b = 6.8640(6) Å β = 100.578(4) °. c = 15.7148(15) Å γ = 90.00 °. Volume 991.31(16) Å3 Z 2 Density (calculated) 1.350 Mg/m3 Absorption coefficient 0.217 mm-1 F(000) 420 Crystal size 0.40 x 0.30 x 0.15 mm3 Theta range for data collection 1.32 to 28.41 °. Index ranges -12 <=h<=11 ,-8 <=k<=7 ,-20 <=l<=20 Reflections collected 4166 Independent reflections 2922 [R(int) = 0.0658 ] Completeness to theta =28.41 ° 0.924 % Absorption correction Empirical Max. and min. transmission 0.9682 and 0.9183 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 4166 / 1 / 262 Goodness-of-fit on F2 0.921 Final R indices [I>2sigma(I)] R1 = 0.0552 , wR2 = 0.1372 R indices (all data) R1 = 0.0958 , wR2 = 0.1601 Absolute Structure Flack parameter x =-0.06(10) Largest diff. peak and hole 0.378 and -0.327 e.Å-3


S9

Influence of the compound 4 geometry on the stereochemical outcome of the

cascade reactions.

Partial equilibration of the double-bond geometry of 3-benzylidenebenzofuran-2(3H)-one 4a (bearing a β-

phenyl group) has been observed under the catalytic reaction conditions of the cascade processes reported

in table 2 and 3 (Figure S1).

NH Ph

OTMSPh

N

N

OMe

NH2

A

OO

Ph20 mol%

oF-C6H4CO2H (20 mol%)

toluene, 40 °C, 24 hsingle E isomer

OO

Ph

OO

Ph

3 : 1

E Z

B

OO

Ph

20 mol%oF-C6H4CO2H (30 mol%)

toluene, 60 °C, 24 hsingle E isomer

OO

Ph

OO

Ph

3 : 1

E Z

Figure S1. Scrambling Experiments

Notably, using a 3:1 mixture of E/Z isomers of compound 4 leads to the same stereochemical outcome as

employing geometrically pure E isomer (compare entries 1 & 2, Table 2, a single stereoisomer, de and ee

>99%).

At the same extent, the stereochemical outcome of cascade reactions depicted in Table 3 is not dependent

on the geometry of the starting compound 4.

The stereo-convergence of the triple cascade depicted in Table 2 might be rationalized on the basis of a

reversible first enamine-catalysed Michael addition step between aldehyde 5 and 4, leading to intermediate

III: a rapid equilibrium may account for a dynamic kinetic resolution process driven by the perfectly suited

matched-pair combination of the chiral iminium ion (generated by condensation of catalyst B and enals 2)

and only one out of the possible eight stereoisomers of intermediate III. Unfortunately, to date we were not

able to isolate this key intermediate.

At present, we cannot rule out a stereo-convergence path driven by a different reactivity of the E and Z

isomers of 4, where the double-bond geometry scrambling continuously regenerates the fast reacting

isomer.

Form a synthetic standpoint, the fact that the geometry of the starting material 4 is not reflected into the

stereochemistry of the final compounds accounts for a more practical synthetic protocol (a mixture of 4 can

be used).


S10

General Procedure for the Organocatalytic Triple Cascade of Aldehydes

proceeding via an Iminium-Iminium-Enamine Sequence (Table 1)

All the reactions were carried out with no precautions to exclude moisture in undistilled toluene. In an

ordinary vial equipped with a Teflon-coated stir bar, (S)-(–)-α,α-Diphenyl-2-pyrrolidinemethanol trimethylsilyl

ether A (0.01 mmol, 20 μL of a 0.5 M toluene stock solution, 5 mol%) was added to 180 μL of toluene. After

the addition of benzoic acid (0.01 mmol, 1.2 mg, 5 mol%), the solution was stirred for 5 minutes at room

temperature before adding the aldehyde 2 (0.6 mmol, 3 equiv). The mixture was then allowed to stir for 5

minutes further at room temperature before the addition of 2-Cumarone 1 (26.8 mg, 0.2 mmol). The vial

was sealed, and the stirring continued at room temperature for 16h. The crude reaction was then flushed

through a short plug of silica, using CH2Cl2/Et2O 1/1 as the eluent. Solvent was removed in vacuo and, after

NMR analysis to determine the diastereomeric ratio of the process, the residue was purified by flash column

chromatography (silica gel) to yield the desired product 3.

(1''R,2''R,3''S)-2-oxo-1'',3''-diphenyl-2H-spiro[benzofuran-3,2''-cyclohex[5']ene]-

6''-carbaldehyde (3a – Table 1, entry 1)

The reaction was carried out following the general procedure to furnish the

crude product (d.r. >19:1 determined by 1H NMR analysis of the crude mixture).

The title compound was isolated as a white solid by column chromatography

(hexane/diethyl ether = 8/2 ) in 75% yield and >99% de and ee. HPLC analysis on a Daicel Chiralpak IC

column: 80/20 hexane/i-PrOH, flow rate 1.00 mL/min, λ = 215, 254 nm: τmajor = 12.9 min, τminor = 23.1 min;

HRMS calcd for (C26H20O3+Na): 403.1310, found 403.1318. [α]25D= -167.7 (c = 1.00, CHCl3, >99% ee).

1H NMR (400 MHz, CDCl3): δ 3.01 (td, 1H, Jd = 20.5 Hz, Jt = 5.7 Hz), 3.38-3.49 (m, 1H), 3.65 (dd, 1H, J1

= 11.4 Hz, J2 = 5.8 Hz), 4.09 (s, 1H), 5.44 (dd, 1H, J1 = 7.7 Hz, J2 = 0.9 Hz), 6.58 (dt, 1H, Jt = 7.6 Hz, Jd

= 0.9 Hz), 6.63-6.79 (m, 2H), 6.87-7.06 (m, 6H), 7.08-7.48 (m, 5H), 9.55 (s, 1H). 13C NMR (400 MHz,

OO

O


S11

CDCl3):・δ 31.3 (CH2), 42.4 (CH), 46.0 (CH), 53.5 (C), 109.9 (CH), 122.9 (CH), 126.7 (CH), 127.3 (C), 127.4

(CH), 128.1 (CH), 128.2 (C), 128.2 (CH), 128.4 (CH), 128.7 (CH), 137.7 (CH), 138.8 (CH), 139.3 (C), 150.6

(CH), 152.5 (C), 177.0 (C), 192.2 (CH).

Carrying out the reaction in the presence of 1 mol% of the catalyst A at 40 degrees afforded similar results:

full conversion, 68% isolated yield, de & ee >99%

(1''S,2''S,3''R)-2-oxo-1'',3''-diphenyl-2H-spiro[benzofuran-3,2''-cyclohex[5']ene]-

6''-carbaldehyde.

The reaction was carried out following the general procedure using (R)-(+)-α,α-

Diphenyl-2-pyrrolidinemethanol trimethylsilyl ether as catalyst to furnish the

crude product (d.r. >19:1 determined by 1H NMR analysis of the crude mixture).

The title compound was isolated as a white solid by column chromatography (hexane/diethyl ether = 8/2 )

in 72% yield and >99% ee. HPLC analysis on a Daicel Chiralpak IC column: 80/20 hexane/i-PrOH, flow rate

1.00 mL/min, λ = 215, 254 nm: τ = minor12.9 min, τmajor = 23.1 min;. [α]25D= +132.9 (c = 1.06, CHCl3, >99%

ee).

(1''R,2''R,3''S)-1'',3''-bis(4-nitrophenyl)-2-oxo-2H-spiro[benzofuran-

3,2''-cyclohex[5']ene]-6''-carbaldehyde (3b – Table 1, entry 3).

The reaction was carried out following the general procedure to

furnish the crude product (d.r. >19:1 determined by 1H NMR

analysis of the crude mixture). The title compound was isolated as

a yellow solid by column chromatography (hexane/diethyl ether = 6/4 ) in 59% yield and >99% de and ee.

HPLC analysis on a Daicel Chiralpak IC column: 70/30 hexane/i-PrOH, flow rate 1.00 mL/min, λ = 215, 254

nm: τmajor = 45.3 min, τminor = 54.1 min; HRMS calcd for (C26H17N2O7): 469.1036, found 469.1048. [α]26D= -

258.5 (c = 1.07, CHCl3, >99% ee).

1H NMR (400 MHz, CDCl3): δ 3.08 (td, 1H, Jd = 20.5 Hz, Jt = 5.4 Hz), 3.45-3.53 (m, 1H), 3.66 (dd, 1H, J1 =

11.3 Hz), 4.21 (s, 1H), 5.50 (dd, 1H, J1 = 7.6 Hz, J2 = 0.9 Hz), 6.67 (dt, 1H, Jt = 7.5 Hz, Jd 0.9= Hz), 6.83-

6.95 (m, 2H), 7.04-7.13 (m, 3H), 7.37-7.50 (m, 2H), 7.88-7.92 (m, 2H), 8.00-8.11 (m, 1H), 8.24-8.36 (m,

1H), 9.57 (s, 1H). 13C NMR (400 MHz, CDCl3): δ 30.8 (CH2), 42.5 (CH), 45.6 (CH), 52.6 (C), 111.0 (CH),

123.4 (CH), 123.5 (C), 123.8 (CH), 125.6 (C), 125.8 (CH), 129.2 (CH), 130.0 (CH), 138.6 (C), 144.7 (C),

145.6 (C), 147.4 (C), 147.8 (C), 150.3 (CH), 152.4 (C), 175.8 (C), 191.5 (CH).

OO

O

NO2

O2N

OO

O


S12

(1''R,2''R,3''S)-1'',3''-bis(4-methoxyphenyl)-2-oxo-2H-spiro[benzofuran-

3,2''-cyclohex[5']ene]-6''-carbaldehyde (3c – Table 1, entry 4).

The reaction was carried out following the general procedure to

furnish the crude product (d.r. >19:1 determined by 1H NMR analysis

of the crude mixture). The title compound was isolated as a pale

yellow solid by column chromatography (hexane/diethyl ether = 7/3 ) in 54% yield and >99% de and ee.

HPLC analysis on a Daicel Chiralpak IC column: 70/30 hexane/i-PrOH, flow rate 1.00 mL/min, λ = 215, 254

nm: τmajor = 18.0 min, τminor = 38.1 min; HRMS calcd for (C28H24O5+Na): 463.1521, found 463.1533. [α]26D= -

215.1 (c = 1.08, CHCl3, >99% ee).

1H NMR (400 MHz, CDCl3): δ 2.98 (td, 1H, Jd = 20.7 Hz, Jt 5.6= Hz), 3.32-3.44 (m, 1H), 3.58 (dd, 1H, J1 =

11.4 Hz, J2 = 5.8 Hz), 3.65 (s, 3H), 3.84 (s, 3H), 4.05 (s, 1H), 5.58 (dd, 1H, J1 = 7.5 Hz, J2 = 1.0 Hz),

6.54-6.58 (m, 2H), 6.59-6.78 (m, 3H), 6.80 (d, 1H, J = 8.0), 6.83-6.87 (m, 2H), 6.91-6.99 (m, 1H),7.02 (dt,

1H, Jd = 1.3 Hz, Jt = 7.7 Hz), 7.11-7.22 (m, 1H), 7.34-7.37 (m, 1H), 9.55 (s, 1H). 13C NMR (400 MHz,

CDCl3):・δ 31.4 (CH2), 41.4 (CH), 45.0 (CH), 53.7 (C), 55.0(CH3), 55.3 (CH3), 109.8 (CH), 113.4 (C), 113.6

(CH), 122.5 (CH), 126.7 (CH), 127.4 (C), 128.5 (CH), 129.1 (CH), 129.7 (C), 130.7 (C), 139.4 (C), 150.3

(CH), 152.4 (C), 158.5 (C), 159.2 (C), 177.0 (C), 192.2 (CH).

(1''R,2''R,3''S)-1'',3''-bis(4-chlorophenyl)-2-oxo-2H-spiro[benzofuran-3,2''-

cyclohex[5']ene]-6''-carbaldehyde (3d – Table 1, entry 5).

The reaction was carried out following the general procedure to furnish the

crude product (d.r. >19:1 determined by 1H NMR analysis of the crude

mixture). The title compound was isolated as a white solid by column

chromatography (hexane/diethyl ether = 7/3 ) in 80% yield and 99% ee. HPLC analysis on a Daicel

Chiralpak IC column: 70/30 hexane/i-PrOH, flow rate 1.00 mL/min, λ = 215, 254 nm: τmajor = 10.4 min, τminor

= 17.8 min; HRMS calcd for (C26H18Cl2O3+Na): 471.0531, found 471.0535. [α]25D= -198.1 (c = 1.32, CHCl3,

99% ee).

1H NMR (400 MHz, CDCl3): δ 3.01 (td, 1H, Jd = 20.4 Hz, Jt 5.2= Hz), 3.35-3.46 (m, 1H), 3.52 (dd, 1H, J1 =

11.4 Hz, J2 = 5.7 Hz), 4.07 (s, 1H), 5.57 (dd, 1H, J1 = 7.7 Hz, J2 = 1.2 Hz), 6.55-6.74 (m, 2H), 6.82-6.90

(m, 3H), 7.00-7.04 (m, 3H), 7.07(dt, 1H, Jd = 1.4 Hz, Jt = 8.0 Hz), 7.12-7.26 (m, 2H), 7.38-7.46 (m, 2H),

9.55 (s, 1H). 13C NMR (400 MHz, CDCl3): δ 31.2 (CH2), 41.8 (CH), 45.3 (CH), 53.1 (C), 110.4 (CH), 122.9

(CH), 126.4 (CH), 126.6 (C), 128.5 (CH), 128.7 (CH), 129.2 (CH), 129.5 (CH), 133.4 (C), 134.2 (C), 136.1

(C), 137.1 (C), 139.1 (C), 150.4 (CH), 152.5 (C), 195.5 (CH).

The absolute configuration of 3d was unambiguously determined by single crystal X-ray

analysis, see page S4.

OO

O

O

O

OO

O

Cl

Cl


S13

(1'R,2'R,6'R)-2',6'-di(furan-2-yl)-2-oxo-2H-spiro[benzofuran-3,1'-cyclohex[3]ene]-3'-

carbaldehyde (3e – Table 1, entry 6).

The reaction was carried out following the general procedure to furnish the crude

product (d.r. >19:1 determined by 1H NMR analysis of the crude mixture). The title

compound was isolated as a white solid by column chromatography (hexane/

diethyl ether = 7/3) in 49% yield and 99% ee. HPLC analysis on a Daicel Chiralpak IC column: 80/20

hexane/i-PrOH, flow rate 1.00 mL/min, λ = 215, 254 nm: τmajor = 15.3 min, τminor = 24.9 min; HRMS calcd for

(C22H16O5+Na): 383.0895, found 383.0913. [α]26D= -163.9 c = 0.84, CHCl3, 99% ee).

1H NMR (400 MHz, CDCl3): δ 2.96 (td, 1H, Jd = 20.9 Hz, Jt = 5.4 Hz), 3.31-3.42 (m, 1H), 4.06 (dd, 1H, J1 =

11.2 Hz, J2 = 5.8 Hz), 4.21 (s, 1H), 5.84 (d, 1H, J = 3.2 Hz), 5.86-5.90 (m, 1H), 6.01 (dd, 1H, J1 = 3.2 Hz,

J2 = 1.8 Hz), 6.08 (d, 1H, J = 3.2 Hz), 6.35 (dd, 1H, J1 = 3.2 Hz, J2 = 1.9 Hz), 6.83 (dt, 1 H, Jt = 7.6 Hz,

Jd = 0.9 Hz), 6.89 (d, 1H, J = 7.9 Hz), 7.02-7.04 (m, 1H), 7.13 (dt, 1H, Jt = 7.6 Hz, Jd = 1.0 Hz), 7.20-7.24

(m, 1H), 7.37-7.39 (m, 1H), 9.51(s, 1H). 13C NMR (400 MHz, CDCl3):・・ 29.6 (CH2), 37.0 (CH), 38.9 (CH),

52.0 (C), 107.2 (CH), 110.1(CH), 110.2 (CH), 110.8 (CH), 110.9 (CH), 123.4 (CH), 125.2 (CH), 127.6

(C), 129.2 (CH), 137.2 (C), 141.9 (CH), 142.1 (CH), 150.2 (CH), 151.4 (C), 152.6 (C), 152.7 (C), 191.7

(CH).

(1'R,2'R,6'R)-2',6'-dimethyl-2-oxo-2H-spiro[benzofuran-3,1'-cyclohex[3]ene]-3'-

carbaldehyde (3f– Table 1, entry 7).


product (d.r. >19:1 determined by 1H NMR analysis of the crude mixture). The title

compound was isolated as a yellowish oil by column chromatography (hexane/diethyl ether = 8/2 ) in 51%

yield and 99% ee. HPLC analysis on a Daicel Chiralpak IC column: 80/20 hexane/i-PrOH, flow rate 1.00

mL/min, λ = 215, 254 nm: τmajor = 13.3 min, τminor = 17.5 min; HRMS calcd for (C16H16O3+Na): 279.0997,

found 297.0994. [α]26D= -21.8 (c = 1.40, CHCl3, 99% ee).

1H NMR (400 MHz, CDCl3): δ 0.74 (d, 3H, J = 6.8 Hz), 1.21 (d, 3H, J = 6.9 Hz), 2.43-2.68 (m, 3H), 2.90 (q,

1H, J = 6.9 Hz), 6.92-6.96 (m, 1H), 7.10-7.22 (m, 3H), 7.30-7.35 (m, 1H), 9.48 (s, 1H).

13C NMR (400 MHz, CDCl3):δ 16.9 (CH3), 17.2 (CH3), 29.3 (CH), 32.1 (CH2), 33.5 (CH), 52.7 (C), 111.0

(CH), 123.7 (CH), 125.7 (CH), 128.9 (C), 129.0 (CH), 142.3 (C), 150.4 (CH), 153.4 (C), 176.6 (C), 193.1

(CH).

OO

O

OO

OO

O


S14

(1'R,2'R,6'R) - diethyl 3'-formyl-2-oxo-2H-spiro [benzofuran-3,1'-cyclohex[3]ene]

-2',6'-dicarboxylate (3g – Table 1, entry 8).


product (d.r. >19:1 determined by 1H NMR analysis of the crude mixture). The

title compound was isolated as a colourless oil by column chromatography

(hexane/acetone = 8/2 ) in 38% yield and 99% ee. HPLC analysis on a Daicel Chiralpak IA column: 80/20

hexane/i-PrOH, flow rate 1.00 mL/min, λ = 215, 254 nm: τmajor = 10.9 min, τminor = 13.5 min; HRMS calcd for

(C20H20O7+Na): 395.1107, found 395.1111. [α]25D= -75.5 (c = 1.23, CHCl3, 99% ee).

1H NMR (400 MHz, CDCl3): δ 0.97 (t, 3, J = 7.2 Hz), 1.10 (t, 3H, J = 7.2 Hz ), 3.02 (td, 1H, Jd = 20.0 Hz, Jt =

5.7 Hz), 3.12-3.23 (m, 1H), 3.71 (s, 1H), 3.85-4.04 (m, 4H), 4.08-4.17 (m, 1H), 7.02-7.18 (m, 3H), 7.24-

7.27 (m, 1H), 7.37 (dt, 1H, Jt = 7.8 Hz, Jd 1.3 = Hz), 9.54 (s, 1H).

13C NMR (400 MHz, CDCl3): δ 13.8 (CH3), 13.9 (CH3), 27.2 (CH2), 42.6 (CH), 45.2 (CH), 46.25 (C), 61.5

(CH2), 61.7 (CH2), 111.2 (CH), 123.9 (CH), 124.0 (CH), 127.1 (C), 130.2 (CH), 135.7 (C), 150.7 (CH), 153.6

(C), 170.2 (C), 171.4 (C), 174.78 (C),191.7 (CH).

General Procedure for the Organocatalytic Triple Cascade proceeding via

enamine – iminium – enamine activation of aldehydes (Table 2)

All the reactions were carried out in an ordinary vial equipped with a Teflon-coated stir bar, with no

precautions to exclude moisture in undistilled toluene. Catalyst A (0.02 mmol, 20 mol %), aldehyde 5 (0.2

mmol) and o-fluoro-benzoic acid (20 mol %) were stirred in toluene (0.2 mL) at room temperature for 10

minutes. The cascade was started by adding a solution of benzofuranone derivative 4 (0.15 mmol) and

aldehyde 2 (0.1 mmol), dissolved in 0.3 mL of toluene. The vial was sealed and heated up to 40 degree, and

stirring was continued till completion of the reaction, as monitored by TLC (generally 48 hours). The crude

reaction was then flushed through a short plug of silica, using CH2Cl2/Et2O 1/1 as the eluent. Solvent was

removed in vacuo and, after NMR analysis to determine the diastereomeric ratio of the process, the residue

was purified by flash column chromatography (silica gel) to yield the desired spiro-compounds 6.

OO

O

O

O

O

O


S15

(6a - Table 2, entry 1). The reaction was carried out at 40°C following the general

procedure to furnish the crude product (d.r. >19:1 determined by 1H NMR analysis of

the crude mixture). The title compound was isolated as a white solid by column

chromatography (hexane/AcOEt = 20/1) in 56% yield and >99% ee. HPLC analysis on a

Daicel Chiralpak IA column: 90/10 hexane/i-PrOH, flow rate 1.0 mL/min, λ = 254 nm: τmajor = 7.56 min, τminor

= 11.2 min. HRMS calcd for (C27H22O3+Na): 417.1467, found 417.1483. [α]rtD= -180.9 (c = 0.57, CHCl3).1H

NMR (400 MHz, CDCl3): δ 1.23 (d, J = 7.2, 3H), 3.15 (d, J = 11.2, 1H), 3.53-3.57 (m, 1H), 4.07 (s, 1H), 5.41

(d, J = 7.2, 1H), 6.57 (t, J = 7.2, 1H), 6.68 (bs, 1H), 6.74 (d, J = 8.4, 1H), 6.88-7.02 (m, 6H), 7.17-7.24 (m,

3H), 7.32 (t, J = 7.2, 1H), 7.42 (bs, 1H), 9.56 (s, 1H).13C NMR (100 MHz, CDCl3): δ 18.7, 34.9, 46.0, 50.0,

54.3, 109.8, 122.5, 126.7, 127.41, 127.46, 128.1, 128.4, 128.6, 137.9, 138.0, 152.4, 156.1, 177.3, 192.4.

(6b - Table 2, entry 3). The reaction was carried out at 40°C following the

general procedure to furnish the crude product (d.r. >19:1 determined by 1H

NMR analysis of the crude mixture). The title compound was isolated as a white

solid by column chromatography (hexane/AcOEt = 20/1) in 57% yield and 99%

ee. HPLC analysis on a Daicel Chiralpak IA column: 95/5 hexane/i-PrOH, flow rate 1.0 mL/min, λ = 254 nm:

τmajor = 10.23 min, τminor = 19.75 min. HRMS calcd for (C27H21ClO3+Na): 451.1077, found 451.1089. [α]rtD= -

148.5 (c = 0.76, CHCl3).1H NMR (400 MHz, CDCl3): δ 1.22 (d, J = 7.2, 3H), 3.13 (d, J = 10.4, 1H), 3.45-3.53

(m, 1H), 4.06 (s, 1H), 5.38 (d, J = 8, 1H), 6.59 (t, J = 7.6, 1H), 6.67 (bs, 1H), 6.77-7.02 (m, 6H), 7.16-7.22

(m, 3H), 7.32 (t, J = 7.2, 1H), 7.40 (bs, 1H), 9.55 (s, 1H).13C NMR (100 MHz, CDCl3): δ 18.7, 34.9, 45.9,

49.4, 54.2, 110.1, 122.7, 126.5, 127.1, 127.5, 128.6, 128.9, 133.2, 136.6, 137.4, 137.9, 152.3, 155.5,

177.0, 192.3.

The absolute configuration of 6b was unambiguously determined by single crystal X-ray


(6c - Table 2, entry 4). The reaction was carried out at 40°C following the

general procedure to furnish the crude product (d.r. >19:1 determined by 1H

NMR analysis of the crude mixture). The title compound was isolated as a

white solid by column chromatography (hexane/AcOEt = 7/1) in 52% yield

and >99% ee. HPLC analysis on a Daicel Chiralpak IA column: 80/20 hexane/i-PrOH, flow rate 1.0 mL/min, λ

= 254 nm: τmajor = 7.37 min, τminor = 13.6 min.. HRMS calcd for (C27H21NO5+Na): 462.1317, found 462.1331.

[α]rtD= -199.9 (c = 0.61, CHCl3).

1H NMR (400 MHz, CDCl3): δ 1.23 (d, J = 7.2, 3H), 3.30 (d, J = 10.4, 1H), 3.54-3.59 (m, 1H), 4.09 (s, 1H),

5.40 (d, J = 8.4, 1H), 6.60 (t, J = 8, 1H), 6.68 (bs, 1H), 6.77 (d, J = 8, 1H), 6.98-7.23 (m, 6H), 7.34 (t, J =

7.2, 1H), 7.41(bs, 1H), 7.88 (d, J = 9.6, 2H), 9.56 (s, 1H).13C NMR (100 MHz, CDCl3): δ 18.7, 34.7, 45.9,

50.0, 54.0, 110.3, 122.9, 123.6, 123.7, 126.4, 126.5, 128.3, 129.3, 137.0, 138.0, 145.9, 147.2, 152.2,

154.6, 176.6, 192.1.

O

Ph

OHC

PhO

O

Ph

OHC

OCl

O

Ph

OHC

ONO2


S16

(6d - Table 2, entry 5). The reaction was carried out at 40°C following the general



chromatography (hexane/AcOEt = 20/1) in 56% yield and >99% ee. HPLC analysis

on a Daicel Chiralpak IA column: 80/20 hexane/i-PrOH, flow rate 1.0 mL/min, λ = 254 nm: τmajor = 5.06 min,

τminor = 6.3 min. HRMS calcd for (C24H24O3+Na): 383.1623, found 383.1605. [α]rtD= -148.2 (c = 0.55, CHCl3).

1H NMR (400 MHz, CDCl3): δ 0.57 (t, J = 8, 3H), 0.88-1.14 (m, 4H), 1.46 (d, J = 7.6, 3H), 2.01-2,06 (m,

1H), 2.96-3.05 (m, 1H), 3.89 (s, 1H), 5.46 (d, J = 7.6, 1H), 6.73 (t, J = 8, 1H), 7.05-7.28 (m, 8H), 9.47 (s,

1H).13C NMR (100 MHz, CDCl3): δ 14.5, 19.2, 21.2, 33.0, 34.7, 41.3, 45.8, 53.4, 110.2, 122.8, 126.4, 127.8,

128.0, 128.1, 128.9, 137.5, 153.0, 156.7, 177.1, 192.4.

(6e - Table 2, entry 6). The reaction was carried out at 40°C following the general




on a Daicel Chiralpak IA column: 95/5 hexane/i-PrOH, flow rate 1.0 mL/min, λ = 254 nm: τmajor = 21.48 min,

τminor = 22.9 min. HRMS calcd for (C24H22O5+Na): 413.1365, found 413.1366. [α]rtD= -97.6 (c = 0.55, CHCl3).

1H NMR (400 MHz, CDCl3): δ 0.81 (t, J = 7.2, 3H), 1.44 (d, J = 8, 3H), 3.01 (d, J = 11.2, 1H), 3.43-3.48

(m, 1H), 3.75-3.83 (m, 2H), 3.99 (s, 1H), 5.50 (d, J = 8, 1H), 6.71 (t, J = 8, 1H), 7.05-7.09 (m, 3H), 7.19-

7.31 (m, 5H), 9.50 (s, 1H).13C NMR (100 MHz, CDCl3): δ 13.6, 18.5, 32.2, 45.1, 50.4, 50.6, 61.3, 110.3,

122.9, 126.2, 126.6, 128.22, 128.29, 129.5, 136.7,137.8, 154.4, 171.2, 192.0.

(6f - Table 2, entry 7). The reaction was carried out at 40°C following the general


the crude mixture). The title compound was isolated as a colorless oil by column

chromatography (hexane/AcOEt = 10/1) in 70% yield and 95% ee. HPLC analysis on

a Daicel Chiralpak IC column: 80/20 hexane/i-PrOH, flow rate 1.0 mL/min, λ = 254 nm: τminor = 6.55 min,

τmajor = 7.12 min. HRMS calcd for (C19H20O5+Na): 351.1208, found 351.1215.[α]rtD= +69.3 (c = 0.61, CHCl3).

1H NMR (400 MHz, CDCl3): δ 0.86 (t, J = 7.6, 3H), 1.21 (d, J = 7.2, 3H), 1.30 (d, J = 7.2, 3H), 2.88 (q, J =

7.2, 1H), 2.99 (d, J = 10.8, 1H), 3.32-3.37 (m, 1H), 3.79-3.89 (m, 2H), 6.78 (d, J = 3.2, 1H), 7.08-7.34 (m,

4H), 9.50 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 13.6, 17.3, 18.5, 32.4, 33.7, 49.9, 50.0, 61.4, 111.0, 123.5,

125.8, 127.5, 129.6, 140.9, 154.1, 171.3, 192.9.

OO

Ph

OHC

OO

CO2EtPh

OHC

OO

CO2Et

OHC


S17

(6g - Table 2, entry 8). The reaction was carried out at 40°C following the general




on a Daicel Chiralpak IA column: 90/10 hexane/i-PrOH, flow rate 1.0 mL/min, λ = 254 nm : τminor = 12.7

min, τmajor = 13.22 min. HRMS calcd for (C26H24O5+Na): 439.1521, found 439.1507. [α]rtD= -99.5 (c = 0.77,

CHCl3). 1H NMR (400 MHz, CDCl3): δ 0.8 (t, J = 7.2, 3H), 2.33-2.41 (m, 1H), 2.65-2.71 (m, 1H), 3.16 (d, J = 12,

1H), 3.50-3.56 (m, 1H), 3.78 (q, J = 7.2, 2H), 3.97 (s, 1H), 5.30-5.35 (m, 2H), 5.51 (d, J = 8.4, 1H), 5.93-

6.03 (m, 1H), 6.7(t, J = 8, 1H), 7.06 (d, J = 7.2, 2H), 7.18-7.31 (m, 6H), 9.50 (s, 1H).13C NMR (100 MHz,

CDCl3): δ 13.5, 36.5, 36.6, 45.1, 48.0, 50.5, 61.3, 110.3, 119.7, 122.9, 126.4, 126.5, 128.20, 128.23, 129.5,

133.6, 136.9, 138.8, 152.2, 153.0, 171.2, 191.9.

General Procedure for the Organocatalytic Tandem double Michael additions

(enamine – iminium activation sequence) (Table 3)

All the reactions were carried out in an ordinary vial equipped with a Teflon-coated stir bar, with no

precautions to exclude moisture in undistilled toluene. Catalyst A (0.02 mmol, 20 mol %), aldehyde 5 (0.2

mmol) and o-fluoro-benzoic acid (20 mol %) were stirred in toluene (0.2 mL) at room temperature for 10

minutes. Catalyst B (0.02 mmol, 20 mol %), enone 7 (0.2 mmol) and o-fluoro-benzoic acid (30 mol %) were

stirred in toluene (0.1 mL) at room temperature for 10 minutes. The cascade was started by adding a

solution of benzofuranone derivative 4 (0.15 mmol) dissolved in 1 mL of toluene. The vial was sealed and

heated up to 60 degrees, and stirring was continued till completion of the reaction, as monitored by TLC

(generally 72 hours). The crude reaction was then flushed through a short plug of silica, using CH2Cl2/Et2O

1/1 as the eluent. Solvent was removed in vacuo and, after NMR analysis to determine the diastereomeric

ratio of the process, the residue was purified by flash column chromatography (silica gel) to yield the desired

spiro-compounds 8.

OO

CO2EtPh

OHC


S18

(8a - Table 3, entry 1).The reaction was carried out at 60°C following the general

procedure to furnish the crude product as a 6.3/1 mixture of diastereoisomers (dr. 6.3:1

determined by integration of 1H NMR signal: δminor 6.45 d, δmajor 6.06 ppm, d). The title

compound was isolated as a white solid by column chromatography (hexane/AcOEt =

90/10) in 70% yield (as a single of diastereoisomer) and >99% ee. HPLC analysis on a

Daicel Chiralpak IC column: 80/20 hexane/i-PrOH, flow rate 1.0 mL/min, λ = 254 nm: τminor = 12.8 min,

τmajor = 15.13 min. HRMS calcd for (C25H20NO3+Na): 391.1310, found 391.1329. [α]rtD= -195.8 (c = 0.76,

CHCl3).1H NMR (400 MHz, CDCl3): δ 2.76 (d, J =13.2, 1H), 2.95 (dd, J = 5.2, 16, 1H), 3.61 (dd, J = 6, 15.6,

1H), 3.68-3.71 (m, 1H), 3.76-3.87 (m, 1H), 6.04 (d, J = 7.2, 1H), 6.73-6.86 (m, 4H), 6.93-6.96 (m, 2H),

7.03-7.07 (m, 4H), 7.24-7.29 (m, 3H).13C NMR (100 MHz, CDCl3): δ 41.8, 42.6, 45.9, 47.5, 110.2,

123.1,126.0, 127.7, 127.9, 128.0, 128.41, 128.49, 129.0, 129.5, 137.3, 139.0, 152.5, 177.9, 209.7.

(8b - Table 3, entry 3). The reaction was carried out at 60°C following the

general procedure to furnish the crude product as a 3.5/1 mixture of

diastereoisomers (d.r. 3.5:1 determined by integration of 1H NMR signal: δmajor

6.25 d, δminor 6.05 ppm. d). The title compound was isolated as a white solid

by column chromatography (hexane/AcOEt = 90/10) in 75% yield (as a 3:1

mixture of diastereoisomers) and 97% ee. HPLC analysis on a Daicel Chiralpak IC column: 80/20 hexane/i-

PrOH, flow rate 1.0 mL/min, λ = 254 nm: Major diastereomer (97% ee): τminor = 13.91 min, τmajor = 14.86

min; Minor diastereomer (>99% ee): τminor = 13.20 min, τmajor = 16.29 min. HRMS calcd for (C25H19ClO3+Na):

425.0920, found 425.0937. [α]rtD= -155.7 (c = 0.78, CHCl3, dr 3.5:1, 97% eemajor, >99% eeminor).

1H NMR (400 MHz, CDCl3): δ 2.73-2.79 (m, 1H), 2.91-2.97 (m, 1H), 2.53-2.67 (m, 3H), 3.54 (dd, J = 6.12,

16.2, 1H), 3.67-3.85 (m, 4H), 6.03 (d, J = 7.6, 1H minor), 6.23 (d, J = 8, 1H major), 6.74-6.93 (m, 8H),

7.0-7.10 (m, 5H), 7.21-7.27 (m, 3H).13C NMR (100 MHz, CDCl3): δ 41.6, 41.7, 42.4, 42.5, 45.3, 46.0, 46.7,

47.4, 55.2, 55.3, 110.45, 110.46, 123.3, 123.4, 125.7, 125.8, 127.62, 127.69, 127.8, 128.0, 128.1, 128.4,

128.5, 128.62, 128.65, 129.27, 129.29, 129.3, 129.4, 130.7, 133.9, 135.8, 136.9, 137.4, 152.5, 177.6,

177.7, 209.1, 209.3.

The absolute configuration of 8b was unambiguously determined by single crystal X-ray


(8c - Table 3, entry 4).The reaction was carried out at 60°C following the

general procedure to furnish the crude product as a 2/1 mixture of

diastereoisomers (d.r. 2:1 determined by integration of 1H-NMR signal: δmajor

6.46 d, δminor 6.08 ppm. d). The title compound was isolated as a white solid

by column chromatography (hexane/AcOEt = 7/1) in 82% yield (as a 2:1

mixture of diastereoisomers) and 98% ee. HPLC analysis on a Daicel Chiralpak IA column: 80/20 hexane/i-

PrOH, flow rate 1.0 mL/min, λ = 254 nm: Major diastereomer (98% ee): τmajor = 13.29 min, τminor = 16.33

OO

O

PhPh

OO

O

PhCl

OO

O

PhNO2


S19

min; Minor diastereomer can’t be separated. HRMS calcd for (C25H19NO5+Na): 436.1161, found 436.1173.

[α]rtD= -240.2 (c = 0.8, CHCl3, dr 2:1, 98% eemajor).

1H NMR (400 MHz, CDCl3): δ 2.75-2.82 (m, 1H), 2.97 (dd, J = 4.76, 16.2, 1H, minor), 3.07 (dd, J = 7.76,

16.56, 1H, major), 3.62 (dd, J = 6.4, 16, 1H, major), 3.45 (dd, J = 5.6, 16.32, 1H, minor), 3.69-3.73 (m,

2H), 3.78-3.96 (m, 4H), 6.05 (d, J = 8, 1H, minor), 6.42 (d, J = 8, 1H, major), 6.73-6.93 (m, 7H), 7.02-

7.05(m, 8H), 7.24-7.30 (m, 3H), 7.90 (d, J = 8.4, 2H, minor), 8.09 (d, J = 8.8, 2H, major).13C NMR (100

MHz, CDCl3): δ 41.1, 41.6, 42.0, 42.1, 45.6, 46.3, 46.7, 47.5, 54.9, 55.6, 110.6, 110.8, 123.5, 123.62,

123.64, 123.8, 125.0, 125.8, 127.0, 127.3, 128.0, 128.1, 128.3, 128.5, 128.6, 129.1, 129.5, 129.6, 129.7,

130.1, 138.4, 144.7, 145.9, 152.4, 152.5, 177.4, 208.3, 208.6.

(8d - Table 3, entry 5).The reaction was carried out at 60°C following the general

procedure to furnish the crude product as a single diastereoisomer. The title

compound was isolated as a white solid by preparative TLC (toluene/AcOEt = 100/1)

in 40% yield (as a single diastereoisomer) and 91% ee. HPLC analysis on a Daicel

Chiralpak IA column: 80/20 hexane/i-PrOH, flow rate 1.0 mL/min, λ = 254 nm: τminor

= 5.67 min, τmajor = 6.23 min; HRMS calcd for (C22H22O3+Na): 357.1467, found 357.1456. [α]rtD= -118.2 (c =

0.55, CHCl3, dr 1.5:1, 98% eemajor, 88% eeminor). 1H NMR (400 MHz, CDCl3): δ 0.78 (t, J = 7.2, 3H), 1.03-1.12 (m, 1H), 1.25-1.43 (m, 3H), 2.53-2.67 (m, 3H),

3.07 (dd, J = 4, 15.6, 1H), 3.55-3.65 (m, 2H), 6.78-6.81 (m, 2H), 6.89 (d, J = 8, 1H), 7.07-7.28 (m, 5H),

7.39 (d, J = 8, 1H).13C NMR (100 MHz, CDCl3): δ 13.9, 20.4, 33.3, 40.5, 42.0, 47.2, 55.8, 110.9, 124.0,

124.9, 127.8, 128.0, 128.3, 128.4, 129.0, 129.3, 137.0, 153.0, 178.1, 209.9.

(8e - Table 3, entry 6).The reaction was carried out at 60°C following the general

procedure to furnish the crude product as a 2.2/1 mixture of diastereoisomers (d.r.

2.2:1 determined by HPLC). The title compound was isolated as a white solid by

column chromatography (hexane/AcOEt = 10/1) in 77% yield (as a 2.2:1 mixture of

diastereoisomers) and 85% ee. HPLC analysis on a Daicel Chiralpak IA column:

90/10 hexane/i-PrOH, flow rate 1.0 mL/min, λ = 254 nm: Major diastereomer (85% ee): τmajor = 16.35 min,

τminor = 17.45 min; Minor diastereomer (>99% ee):τmajor = 14.7 min, HRMS calcd for (C22H20O5+Na):

387.1208, found 428.1225. [α]rtD= -57.2 (c = 0.58, CHCl3,).

1H NMR (400 MHz, CDCl3): δ 1.0 (t, J = 7.2, 3H), 2.63-2.68 (m, 1H), 2.80-2.86 (m, 1H), 3.32 (dd, J = 5.6,

16, 1H), 3.42-3.63 (m, 2H), 6.75-6,91 (m, 3H), 7.06-7.29 (m, 6H).13C NMR (100 MHz, CDCl3): δ 13.73,

13.76, 38.3, 39.6, 41.9, 42.2, 46.4, 46.6, 50.60, 50.61, 52.3, 52.5, 61.6, 61.8, 110.6, 110.7, 122.2, 123.9,

124.1, 124.4, 127.9, 128.0, 128.2, 128.40, 128.44, 129.4, 129.8, 136.2, 136.3, 153.0, 153.2, 170.0, 170.8,

175.7, 176.7, 206.2, 207.2.

OO

Ph

O

OO

CO2EtPh

O


S20

(8f - Table 3, entry 7).The reaction was carried out at 60°C following the


diastereoisomers (d.r. 3.5:1 determined by integration of 1H NMR signal:

δmajor 6.05 d, δminor 6.24 ppm. d). The title compound was isolated as a

white solid by column chromatography (hexane/AcOEt = 85/15) in 85%

yield (as a 3.4:1 mixture of diastereoisomers) and 97% ee. HPLC analysis on a Daicel Chiralpak IC column:

8/2 hexane/i-PrOH, flow rate 1.0 mL/min, λ = 254 nm: Major diastereomer (97% ee): τminor = 12.9 min,

τmajor = 15.9 min; Minor diastereomer (96% ee): τminor = 13.5 min, τmajor = 14.5 min. HRMS calcd for

(C25H19Cl O3+Na): 425.0920, found 425.0938. [α]rtD= -130.6 (c = 1.07, CHCl3, dr 4:1, 97% eemajor, 96%

eeminor). 1H NMR (400 MHz, CDCl3): δ 2.71-2.84 (m, 1H), 2.91-3.01 (m, 1H), 3.53.3.88 (m, 4H), 6.05 (d, 1H, J = 7.5

Hz major), 6.24 (d, 1H, J = 7.5 Hz minor), 6.75.-6.98 (m, 6H), 7.01-7.13 (m, 3H), 7.22-7.34 (m, 3H) ppm. 13C NMR (100 MHz, CDCl3): δ 41.7 (CH2), 42.5 (CH2), 45.3 (CH), 47.5 (CH), 55.3 (C), 110.5 (CH), 123.3

(CH), 125.8 (CH), 127.6 (C), 128.0 (CH), 128.1 (CH), 128.5 (CH), 128.6 (C), 128.6 (C), 128.7 (C), 129.3

(CH), 129.4 (CH), 129.5 (CH), 130.8 (C), 133.7 (C), 135.9 (C), 138.8 (C), 152.5 (C), 177.7 (C), 209.2 (C)

ppm.

(8g - Table 3, entry 8).The reaction was carried out at 60°C following the


diastereoisomers (d.r. 4:1 determined by integration of 1H-NMR signal: δmajor 6.02

d, δminor 6.07 ppm. d). The title compound was isolated as a white solid by

column chromatography (hexane/Acetone = 95/5) in 91% yield (as a 4:1 mixture

of diastereoisomers) and 96% ee. HPLC analysis on a Daicel Chiralpak IA column: 95/5 hexane/i-PrOH, flow

rate 1.0 mL/min, λ = 254 nm: Major diastereomer (96% ee): τminor = 18.7 min, τmajor = 24.4 min; Minor

diastereomer (93% ee): τminor = 17.3 min, τmajor = 19.6 min. [α]rtD= -99.1 (c = 0.78, CHCl3, dr 4:1, 96%

eemajor, 93% eeminor). 1H NMR (400 MHz, CDCl3): δ 2.72-2.95 (m, 2H), 3.54.3.84 (m, 4H), 3.94 (dd, 1H, J1 = 13.7, J2= 4.2 Hz),

6.02 (d, 1H, J = 7.5 Hz major), 6.07 (d, 1H, J = 7.5 Hz minor), 6.47 (dd, 1H, J1= 5.2, J2= 1.4 Hz ), 6.70-

6.73 (m, 1H), 6.75-6.88 (m, 2H), 6.91-6.94 (m, 2H), 6.99 (dd, 1H, J1= 4.9, J2= 2.9 Hz), 7.02-7.16 (m, 2H),

7.26-7.30 (m, 2H) ppm. 13C NMR (100 MHz, CDCl3): δ 41.5 (CH), 41.8 (CH2), 42.9 (CH2), 47.3 (CH), 55.1 (C), 110.4 (CH), 122.9

(CH), 123.3 (CH), 125.7 (C), 125.8 (CH), 125.9 (CH), 126.8 (CH), 128.0 (C), 128.1 (CH), 128.5 (CH), 128.6

(CH), 129.1 (CH), 129.5 (CH), 138.2 (C), 139.1 (C), 139.7 (C), 152.8 (C), 177.9 (C), 209.3 (C) ppm.

OO

O

Cl

OO

O

S


S21

1.38 (t, J = 7.2, 3H), 4.35 (q, J = 7.2, 2H), 6.92 (s, 1H), 7.13 (d, J = 8, 1H), 7.21 (td, J = 0.92, 7.6, 1H), 7.47 (td, J = 1.48, 7.8, 1H), 8.60 (d, J = 7.6, 1H)ppm

OO

EtO2C


S22

OO

O

3aO

O

O

3a

OO

O

3a


S23

OO

O

NO2

O2N

3b

OO

O

NO2

O2N

3b


S24

OO

O

O

O

3c

OO

O

O

O

3c


S25

OO

O

Cl

Cl

3d

OO

O

Cl

Cl

3d


S26

OO

OO

O

3e

OO

OO

O

3e


S27

OO

O

3g

OO

O

3g


S28

OO

O

O

O

O

O

3h

OO

O

O

O

O

O

3h


S29


S30


S31


S32


S33


S34


S35


S36


S37


S38


S39


S40


S41

OO

OCl

8f

OO

OCl

8f


S42

OO

O

8g

S

OO

O

8g

S


S43

OO

O

Racemic

OO

O

3a obtained using cat. (S)-A


S44

OO

O

obtained using cat. (R)-A


S45

OO

O

NO2

O2N

Racemic

OO

O

NO2

O2N

3b


S46

OO

O

O

O

Racemic

OO

O

O

O

3c


S47

OO

O

Cl

Cl

Racemic

OO

O

Cl

Cl

3d


S48

OO

OO

O

Racemic

OO

OO

O

3e


S49

OO

O

Racemic

OO

O

3g


S50

OO

O

O

O

O

O

Racemic

OO

O

O

O

O

O

3h


S51


S52


S53


S54


S55


S56


S57


S58


S59


S60


S61


S62


S63

OO

OCl

-8fRacemic

OO

O

Cl

8f


S64

-8gO

O

O

Racemic

S

OO

O

8g

S


multiple approaches to enantiopure spirocyclic

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